BRAF V600 Mutation Appears to Be Targetable Oncogene in Some but Not All Nonmelanoma Cancers


Key Points

  • Vemurafenib was active in BRAF V600–mutant NSCLC and Erdheim-Chester disease and Langerhans’-cell histiocytosis.
  • Histologic context appears to be an important determinant of response in BRAF V600–mutant disease.

In a phase II histology-independent basket study reported in The New England Journal of Medicine, Hyman et al found that the BRAF V600 kinase inhibitor vemurafenib (Zelboraf) exhibited activity in some but not all nonmelanoma cancers with BRAF V600 mutations.

Study Details

In the study, 122 patients with BRAF V600–mutant cancers were enrolled in six prespecified cohorts and a cohort comprising all other tumor types. All patients received vemurafenib monotherapy (960 mg twice daily) except those with colorectal cancer, who received vemurafenib alone or with cetuximab (Erbitux). The primary endpoint was response rate.


In the six predefined cohorts, response was achieved in 8 (42%) of 20 patients with non–small cell lung cancer (NSCLC), 0 (0%) of 10 with colorectal cancer receiving vemurafenib alone and 1 (4%) of 27 receiving vemurafenib/cetuximab, 1 (12%) of 8 with cholangiocarcinoma, 6 (43%) of 18 with Erdheim-Chester disease or Langerhans’-cell histiocytosis, and 2 (29%) of 7 with anaplastic thyroid cancer.

Median progression-free survival in NSCLC patients was 7.3 months. Median treatment duration was 5.9 months in patients with Erdheim-Chester disease or Langerhans’-cell histiocytosis, with no patients exhibiting disease progression. Responses were also observed in three of four patients with anaplastic pleomorphic xanthoastrocytoma and in one patient each with salivary-duct cancer, soft-tissue sarcoma, and ovarian cancer. Response has persisted for > 12 months in one patient with anaplastic thyroid cancer, one with cholangiocarcinoma, and one with ovarian cancer.

The most common adverse events of any grade with vemurafenib monotherapy were rash (68%), fatigue (56%), and arthralgia (40%).

The investigators concluded: “BRAF V600 appears to be a targetable oncogene in some, but not all, nonmelanoma cancers. Preliminary vemurafenib activity was observed in non–small-cell lung cancer and in Erdheim–Chester disease and Langerhans’-cell histiocytosis. The histologic context is an important determinant of response in BRAF V600–mutated cancers.”

José Baselga, MD, PhD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the New England Journal of Medicine article.

David M. Hyman, MD, of Memorial Sloan Kettering Cancer Center, Igor Puzanov, MD, of Vanderbilt University Medical Center, and Vivek Subbiah, MD, of The University of Texas MD Anderson Cancer Center, and Josep Tabernero, MD, PhD, of Vall d’Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, and Dr. Baselga contributed equally to the article.

The study was funded by F. Hoffmann–La Roche/Genentech. For full disclosures of the study authors, visit

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